Vaccines aid in saving lives from infectious diseases and biological warfare attacks. They should be safe and effective in all recipients; otherwise, the likelihood that those who are hyporesponsive to vaccines will transmit disease to vulnerable individuals and disrupt herd immunity is greatly increased. There is compelling evidence that smokers, who represent more than one billion people worldwide, are less responsive to vaccines (1-3). However, there currently is no scientific organization and commercial entity offering an enhanced vaccine or working on such optimization. We made progress in our understanding of the mechanisms that underlie the impairment of vaccine-induced immunity and reported that prophylactic and therapeutic vaccines fail to protect and cure animals from disease due to nicotine-induced defects in the biological activities of dendritic cells (DCs) (4). We also reported that the defects observed in DCs are reversible and IFN-g known to be produced by natural killer (NK) cells, is an absolute requirement in this process (5). Hence, we hypothesize that an adjustment of vaccine formulation with immunological adjuvant(s) capable of restoring interactions between DC and NK cells will allow vaccines to also work optimally in this population. Of note, our new preliminary data revealed that among TLR agonists tested, nicotine has limited adverse effect on DC and NK cells responses to a TLR7/8 agonist (Fig. 2). Importantly, addition of this agonist to the vaccine formulation significantly improves antigen-specific effector memory Th1 response in nicotine-exposed mice (Fig. 3C). Based on these findings, we propose to identify the signature of adjuvant(s) that can overcome the degrading effects of nicotine on vaccination outcome. The following aim is designed to accomplish this objective. Aim: Determine the mechanisms by which the TLR7/8 agonist in contrast to other TLR agonists restores the efficacy of vaccines in nicotine-exposed hosts. At the completion of this study, we will have revealed the unknown mechanisms underlying the differential effectiveness of TLR agonists in nicotine-exposed hosts. We envision that such findings could be applied to further development of current and future vaccines.